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BackgroundCentral nervous system tumors are now the most common primary neoplasms seen in children, and radiation therapy is a key component in management. Secondary malignant neoplasms (SMNs) are rare, but dreaded complications. Proton beam therapy (PBT) can potentially minimize the risk of SMNs compared to conventional photon radiation therapy (RT), and multiple recent studies with mature data have reported the risk of SMNs after PBT. We performed this systematic review and meta-analysis to characterize and compare the incidence of SMNs after proton and photon-based radiation for pediatric CNS tumors.MethodsA systematic search of literature on electronic (PubMed, Cochrane Central, and Embase) databases was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) method. We included studies reporting the incidence and nature of SMNs in pediatric patients with primary CNS tumors. The crude incidence of SMNs and all secondary neoplasms were separately extracted, and the random-effects model was used for pooled analysis and subgroup comparison was performed between studies using photons vs. protons.ResultsTwenty-four studies were included for analysis. A total of 418 SMNs were seen in 38,163 patients. The most common SMN were gliomas (40.6%) followed by meningiomas (38.7%), sarcomas (4.8%), and thyroid cancers (4.2%). The median follow-up was 8.8 years [3.3–23.2].The median latency to SMN for photons and protons were 11.9 years [5-23] and 5.9 years [5-6.7], respectively. The pooled incidence of SMNs was 1.8% (95% CI: 1.1%–2.6%, I2 = 94%) with photons and 1.5% (95% CI: 0%–4.5%, I2 = 81%) with protons. The pooled incidence of all SNs was not different [photons: 3.6% (95% CI: 2.5%–4.8%, I2 = 96%) vs. protons: 1.5% (95% CI: 0–4.5%, I2 = 80%); p = 0.21].ConclusionWe observed similar rates of SMN with PBT at 1.5% compared to 1.8% with photon-based RT for pediatric CNS tumors. We observed a shorter latency to SMN with PBT compared to RT. With increasing use of pencil beam scanning PBT and VMAT, further studies are warranted to evaluate the risk of secondary cancers in patients treated with these newer modalities.

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Background Brainstem toxicity after radiation therapy (RT) is a devastating complication and a particular concern with proton radiation (PBT). We investigated the incidence and clinical correlates of brainstem injury in pediatric brain tumors treated with PBT. Methods All patients <21 years with brain tumors treated with PBT at our institution from 2007–2019, with a brainstem Dmean >30 Gy and/or Dmax >50.4 Gy were included. Symptomatic brainstem injury (SBI) was defined as any new or progressive cranial neuropathy, ataxia and/or motor weakness with corresponding radiographic abnormality within brainstem. Results A total of 595 patients were reviewed and 468 (medulloblastoma=200, gliomas=114, ependymoma=87, ATRT=43) met our inclusion criteria. Median age at RT was 6.3 years and median prescribed RT dose was 54Gy [RBE]. Fifteen patients (3.2%) developed SBI, at a median of 4 months after RT. Grades 2,3,4 and 5 brainstem injuries were seen in 7,5,1 and 2 patients respectively. Asymptomatic radiographic changes were seen in 51 patients (10.9%). SBI was significantly higher in patients with age ≤3 years, female gender, ATRT histology, patients receiving high dose chemotherapy with stem cell rescue and those not receiving craniospinal irradiation. Patients with SBI had a significantly higher V50-52. In 2014, our institution started using strict brainstem dose constraints (Dmax ≤57 Gy, Dmean ≤52.4 Gy and V54≤10%). There was a trend towards decrease in SBI from 4.4% (2007-2013) to 1.5% (2014-2019) (p=0.089) without affecting survival. Conclusion Our results suggest a low risk of SBI after PBT for pediatric brain tumors, comparable to photon therapy. A lower risk was seen after adopting strict brainstem dose constraints.